Electrophilic trifluoromethylation of carbonyl compounds and their nitrogen derivatives under copper catalysis

Abstract

Recent advances in electrophilic trifluoromethylation reactions of carbonyl compounds and their usual surrogates are highlighted with particular focus on copper-catalysed (or mediated) C-CF3 bond forming reactions. Ketones and aldehydes (notably via their enol ether and enamine derivatives) enable electrophilic trifluoromethylation at the α-carbon of the carbonyl compounds, whereas aldehyde N,N-disubstituted hydrazones undergo electrophilic attack of the cationic or radical CF3 species at the azomethine carbon, thus providing an umpolung alternative to nucleophilic trifluoromethylation of carbonyl compounds. A reversal in reactivity is also observed for conjugated systems. While α,β-unsaturated ketones regioselectively incorporate the CF3 moiety at the α-position of the enones, trifluoromethylation occurs preferentially at the olefinic β-carbon of the corresponding hydrazones.

Synthesis of α‐Trifluoromethylated Ketones from Vinyl Triflates in the Absence of External Trifluoromethyl Sources

“…After 2h, BEt 3 (1.0 m in hexanes, 0.25 mL) was added and the reaction mixture was stirred for 14 ha tr oom temperature before water (3 mL) was added, and the resulting mixture was extracted with dichloromethane (3 10 mL). After 2h, BEt 3 (1.0 m in hexanes, 0.25 mL) was added and the reaction mixture was stirred for 14 ha tr oom temperature before water (3 mL) was added, and the resulting mixture was extracted with dichloromethane (3 10 mL).…”

“…[1] Over the past decade,considerable effort has been dedicated to the efficient introduction of trifluoromethyl groups. [3] Thenucleophilic trifluoromethylation of a-haloketones with CuCF 3 has recently been reported by Grushin et al (Scheme 1b), [4] while the radical trifluoromethylation of enolates is well established (Scheme 1c). For the preparation of such trifluoromethylated ketones,s everal methods have been developed.…”

“…(0.3 mmol, 0.33 m), BEt3 (1 m in hexanes, 0.15 mL, 0.5 equiv), CH 2 ClCH 2 Cl (1 mL). [b] Determined by 1 HNMR spectroscopy using 1,1,2,2-tetrachloroethane as an internal standard.…”

Synthesis of α‐Trifluoromethylated Ketones from Vinyl Triflates in the Absence of External Trifluoromethyl Sources

“…Fore xample,t he use of the Umemoto reagent and the Togni reagent efficiently achieves the electrophilic trifluoromethylation of enolates (Scheme 1a). [3] Thenucleophilic trifluoromethylation of a-haloketones with CuCF 3 has recently been reported by Grushin et al (Scheme 1b), [4] while the radical trifluoromethylation of enolates is well established (Scheme 1c). In 1990, Oshima, Utimoto,a nd co-workers reported the first radical trifluoromethylation of silyl or germyl enol ethers initiated by triethylborane (BEt 3 ), [5] and the scope of this radical trifluoromethylation was subsequently extended by Mikami and coworkers,w ho used other initiators.…”

Taming Radical Intermediates for the Construction of Enantioenriched Trifluoromethylated Quaternary Carbon Centers

“…[1,3,5,6] This is as urprising fact given the growing prevalence of the CF 3 group in medicinal and agrochemistry and the concomitantly ever growing body of literature focused on mild, selective,a nd efficient trifluoromethylation methodologies,often via the use of electrophilic radical species. [2] While the first catalytic enantioselective radical trifluoromethylation was reported in 2009 by the group of Macmillan, the major drawback to the protocol was the use of gaseous CF 3 I. [3] In contrast, the hypervalent iodinebased reagents 1 and 2 (Scheme 1), developed in 2006, have found widespread use in academia as crystalline,b enchstable,a nd easy to synthesize precursors to electrophilic CF 3 radical species.…”